The ovarian function of mammalian females is regulated by pituitary hormones, called gonadotropins. The best known gonadotropins are follicle stimulating hormone (FSH), which causes follicle maturation, and luteinising hormone (LH), which causes ovulation.
After each menses the ovaries are stimulated by FSH released by the pituitary to grow a cohort of follicles. These follicles each comprise an oocyte (egg cell) which is enveloped by an orb of granulosa cells. During growth of the follicles several layers of granulosa cells are being formed. Gradually, one follicle becomes dominant and the others become atretic and degenerate by apoptosis. Follicle maturation during the normal menstrual cycle occurs in 12-14 days. As the number of granulosa cells increases, more estrogen is secreted by these cells.
Once the dominant follicle has reached maturity, the follicle will burst (ovulate) under the action of a surge of LH which is released by the pituitary in response to the increased blood serum estrogen level (positive feedback). The oocyte is discharged from the follicle into the ampulla of the Fallopian tube, where fertilization may take place. The oocyte or embryo is transported to the uterus in 5-7 days, where implantation may occur in the midluteal phase.
The follicle which has discharged the oocyte is transformed into a new hormone producing organ, the corpus luteum. The corpus luteum produces progesterone together with estrogens. The corpus luteum has a limited lifespan of about 12-14 days. After said period, it ceases to function, and as a result the blood level of estrogens and progesterone drops. This decline of progesterone causes necrosis of the lining of the uterus and thus menstruation.
In particular in the area of ovulation induction, the past decades have shown the development and commercial introduction of numerous drugs assisting in fertility management of infertile couples. Amongst others, these include anti-estrogens (like clomiphene citrate and tamoxifen citrate), pulsatile GnRH, purified and recombinant gonadotropins, and GnRH agonists and antagonists. The specific drugs used and administration regimens chosen largely depend on the goal of the treatment, e.g. induction of mono-ovulation in anovulatory females or controlled ovarian hyperstimulation (COH) to induce multiple follicular development as an element in assisted reproductive technologies (ART). Examples of ART methods that are widely used to treat female and/or male factor infertility include intrauterine insemination (IUI) and in vitro fertilization (IVF). IVF can be performed with and without intracytoplasmatic sperm injection (ICSI) and includes a subsequent embryo transfer step.
COH is nowadays widely used in ART. First results with COH were disappointing as a result of the occurrence of premature LH surges in about 30% of the cases. Such a premature LH-surge may incite ovulation of oocytes which have not yet reached maturity and/or it may frustrate harvesting of oocytes for in vitro fertilisation (IVF). It was found that the introduction of GnRH agonists allowed the prevention of premature LH surges as well as programmation of the treatment cycles. To date GnRH agonists are used in most of the cycles. However, GnRH agonists are inconvenient (long treatment period), may induce ovarian cysts, are expensive and not devoid of adverse effects (side effects, increased incidence of Ovarian HyperStimulation Syndrome (OHSS), etc.).
Recently GnRH antagonists were introduced to prevent premature LH surges and to avoid the problems related to the use of GnRH agonists. WO 98/58657 (AKZO NOBEL) suggests that a daily dose of between 0.125 mg and 1 mg ganirelix prevents premature LH rises to occur and at the same time maintains sufficient LH to support follicular maturation and estrogen biosynthesis. Likewise CN 1 199 642 (ASTA Medica) describes the daily subcutaneous administration of cetrorelix in an amount of 0.1-0.5 mg to selectively suppress the secretion of LH.
However, there are concerns about the pregnancy rates observed with protocols using GnRH antagonists. Several studies have indicated that pregnancy rates for GnRH antagonists are lower than those achieved with GnRH agonists. WO 01/00227 (AKZO NOBEL) which was published recently, reports that it has been found that there is no relationship between the implantation rate and level of LH, but that there exists a relationship between the GnRH antagonist levels and implantation rate. It is advocated in said application to administer GnRH antagonist in an amount depending on the body weight. The advocated levels are between 128 and 264 μg per day.
From the above it will be evident that the successful use of GnRH antagonist depends on accurately establishing the adequate dose to effectively prevent an LH-surge without lowering endogenous LH-levels too much. Since the adequate dose is very much dependent on individual physiological attributes, such as bodyweight, the use of a fixed dosage for all females is bound to lead to premature LH-surges in some of them, and bad implantation and pregnancy rates in others. This means that in order to achieve high success rates of treatment, it is necessary to adjust dosages on an individual basis. However, individual adjustment of the dosage levels as proposed in WO 01/00227 has the disadvantage that self administration is no longer an option, or that an assortment of dosage units containing different amounts of GnRH-antagonist is required.
Thus, there is a need for a robust COH method that employs a GnRH antagonist and that performs at least as well as similar methods using GnRH agonists, in terms of prevention of LH-surges and implantation and pregnancy rates.